HOPE - HIV Obstruction by Programmed Epigenetics

HOPE - 通过编程表观遗传学阻断 HIV

• 批准号: 10469610
• 负责人: Lishomwa C Ndhlovu
• 金额: $ 533.6万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469610
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adopted; Africa; Architecture; Biology; Blood; Brazil; Cells; Cerebrospinal Fluid; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Community Health Education; DNA; Detection; Endogenous Retroviruses; Ensure; Epigenetic Process; Excision; Face; Failure; Foundations; Funding; Gene Silencing; Genome engineering; Gifts; Goals; Gut associated lymphoid tissue; HIV; HIV-1; Health; Health Services; Human; Human Genome; Immunosuppression; Industry; Infection; Intake; Integration Host Factors; Learning; Leukapheresis; Life; Longevity; Military Personnel; Mission; Molecular; Morbidity - disease rate; Mutation; Myeloid Cells; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; Obstruction; Peptide Nucleic Acids; Persons; Pharmaceutical Preparations; Proviruses; Public Health; Research; Research Personnel; Research Support; Risk; Sampling; San Francisco; Science; Source; Stem cell transplant; Suggestion; T-Lymphocyte; Technology; Testing; Tissues; Toxic effect; Translations; United States National Institutes of Health; Viral; Viral Load result; Viral reservoir; Virion; Virus; Virus Latency; Virus Replication; Work; antiretroviral therapy; antiviral immunity; base; base editor; cell type; cohort; collaboratory; combinatorial; comorbidity; cortistatin; expectation; improved; industry partner; inhibitor; innovation; integration site; latent HIV reservoir; lymph nodes; member; mortality; next generation; novel; novel strategies; organizational structure; prevent; programs; recombinase; restoration; social stigma; success; tool; viral rebound

PROJECT SUMMARY/ABSTACT After 40 years, a cure for people living with HIV (PLWH) remains both elusive and one of NIAID/NIH’s highest priorities. Rebound-competent latent reservoir cells persist despite antiretroviral therapy and rekindle infection due to the lack of efficient proviral silencing. The underlying hypothesis of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory application is a novel “block-lock-excise” approach—that entails the long-term durable silencing of viral expression towards permanent excision of the latent provirus—will lead to the permanent control of the virus in the absence of therapy. A graded transformation of remnant HIV in PLWH is proposed from latent into silent to permanently defective proviruses, thus emulating and accelerating the natural path that human endogenous retroviruses have taken in the human genome over millions of years. This hypothesis was formulated on the basis of 30+ years of dedicated research by HOPE investigators into the underlying mechanisms of HIV latency, lack of success to date with latency-reversing strategies, recent results with Tat inhibitor didehydro-Cortistatin A (dCA) and ELITE controllers showing that a successful ‘functional’ HIV cure could arise if there is a deep silencing of reservoir virus, and the availability of advanced genome- engineering technologies (Brec1 recombinase, peptide nucleic acids, CRISPR-base editors) for direct delivery of the final coup de grace: excision of remnant virus for permanent cure. The central hypothesis will be tested in three Research Focuses (RFs) and five central objectives shared between the three RFs. Specific Aim (RF) 1: Define mechanistically the durable transcriptional silencing of HIV across all T- and myeloid cell subsets by combinatorial targeting of key host and viral factors. Specific Aim (RF) 2: Develop and characterize next- generation HIV silencing approaches in the control of HIV rebound. Specific Aim (RF) 3: Disable the silenced HIV-1 provirus by targeted genome engineering. Objective 1: Determine the epigenetic architecture of the integrated provirus at different integration sites that prevents permanent silencing of latent HIV. Objective 2: Define, at the molecular level, cell types and epigenetic cell states that favor viral rebound. Objective 3: Identify molecular functions of Tat and host factors that prevent permanent silencing. Objective 4: Learn from HERV silencing and mutational decay in the human genome. Objective 5: Respond to community expectations around ‘functional’ and ‘classical’ cure approaches. The HOPE Collaboratory partnered with the San Francisco AIDS Foundation to build a strong art-based community education program and with three primary industry leaders, Amgen, Sangamo and Constellation, who will provide intellectual and materialistic support. We also engaged with four clinical cohorts of PLWH for clinical sample analysis in the US, Brazil and Africa. Collectively, the innovative science, renowned members, collaborative organizational structure and milestone- driven research plan of the HOPE Collaboratory represents a new and substantive departure from the status quo and promises a fundamental new approach to HIV Cure strategies.

项目概要/摘要 40年后，治愈艾滋病毒感染者（PLWH）仍然是难以捉摸的，也是NIAID/NIH的最高目标之一。 优先事项尽管接受抗逆转录病毒治疗，但具有反弹能力的潜在储库细胞仍然存在，并重新引发感染 因为缺乏有效的前病毒沉默。艾滋病毒程序性阻断的基本假设 表观遗传学（HOPE）合作实验室应用是一种新的“阻断-锁定-切除”方法-需要长期的 病毒表达的持久沉默朝向潜伏前病毒的永久切除-将导致 在没有治疗的情况下永久控制病毒。PLWH中残留HIV的分级转化是 提出从潜伏到沉默到永久有缺陷的前病毒，从而模仿和加速自然 这是人类内源性逆转录病毒在人类基因组中数百万年来所走的道路。这 这一假设是在HOPE研究人员30多年的专门研究基础上制定的， HIV潜伏期的潜在机制，迄今为止潜伏期逆转策略缺乏成功，最近的结果 与达特抑制剂双脱氢皮质抑素A（dCA）和ELITE控制器显示，成功的“功能性”艾滋病毒 如果能使宿主病毒深度沉默，并获得先进的基因组， 工程技术（Brec 1重组酶、肽核酸、基于CRISPR的编辑器）用于直接递送 最后的致命一击：切除残余病毒以永久治愈。中心假设将在 三个研究重点（RF）和五个中心目标之间共享的三个RF。特定目标（RF）1： 通过以下方式在机制上定义HIV在所有T细胞和髓系细胞亚群中的持久转录沉默： 关键宿主和病毒因子的组合靶向。具体目标（RF）2：开发和表征下一个- 新一代HIV沉默方法在控制HIV反弹中的应用。特定目标（RF）3：禁用静音 通过靶向基因组工程的HIV-1前病毒。目的1：确定表观遗传结构的 整合的前病毒在不同的整合位点，防止永久沉默潜伏的艾滋病毒。目标二： 在分子水平上定义有利于病毒反弹的细胞类型和表观遗传细胞状态。目标3：识别 防止永久沉默的达特和宿主因子的分子功能。目标4：向HERV学习 沉默和突变衰退。目标5：满足社区的期望 “功能性”和“经典”治疗方法。希望合作实验室与旧金山弗朗西斯科中心合作， 基金会建立一个强大的艺术为基础的社区教育计划，并与三个主要行业领导者， 安进、桑加莫和星座，他们将提供智力和物质支持。我们还参与了 在美国、巴西和非洲进行临床样本分析的四个PLWH临床队列。统称 创新的科学、知名的成员、协作的组织结构和里程碑式的研究 希望合作实验室的计划代表了一种新的、实质性的脱离现状和承诺的做法 艾滋病治疗战略的基本新方法。